Non-canonical functions of autophagy proteins

自噬蛋白的非典型功能

• 批准号: 10163773
• 负责人: DOUGLAS R GREEN
• 金额: $ 44.88万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163773
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Age; Alpha Particles; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Apoptotic; Autophagocytosis; Autophagosome; Bacteria; Biochemical; Biochemistry; Biological; Biology; Brain; Cell membrane; Cell physiology; Cell-Free System; Cells; Complex; Defect; Degenerative Disorder; Dendritic Cells; Digestion; Disease; Elements; Endocytosis; Endosomes; Epithelial Cells; Event; Generations; Health; Immune response; Immune system; Inflammation; Inflammatory; Inflammatory Response; Investigation; Ligase; Link; Lipids; Lysosomes; Membrane; Microbe; Microglia; Modality; Molecular; Myelogenous; Myeloid Cells; Natural Immunity; Nematoda; Neurodegenerative Disorders; Nutrient; Outcome; Pathway interactions; Phagocytes; Phagocytosis; Phagosomes; Phosphotransferases; Physiological; Process; Protein Family; Proteins; Recruitment Activity; Recycling; Role; Surface; Therapeutic; autoinflammatory; base; experimental study; fly; fungus; in vivo; lupus-like; macrophage; neuroinflammation; novel; pathogen; receptor; receptor recycling; recruit; response; tool

The ancient processes of phagocytosis and autophagy co-evolved as mechanisms of nutrient acquisition and pathogen defense, and under some circumstances their functional machineries intersect. This is the case for LC3-associated phagocytosis (LAP), a process in which some components of the autophagy pathway are recruited to the phagosome to lipidate LC3 molecules on this single membrane. LAP and canonical autophagy are distinct at the molecular, cellular, and organismal levels. Since we discovered this process eleven years ago, LAP has been implicated in immune responses to a variety of bacteria and fungi, and in several other physiological and disease settings. We have also identified a related, but distinct process of LC3-associated endocytosis (LANDO), which functions in the endocytosis of b-amyloid involved in Alzheimer’s Disease (AD). This application will explore the mechanisms of LAP and LANDO and their roles in myeloid responses in AD. We have chosen an AD model in which to interrogate the impact of LAP/LANDO defects in myeloid cells in vivo, and the core biochemistry of LAP in cell-free systems. We envision three aims of this project. 1. What are the mechanisms of LAP that distinguish it from conventional autophagy? Because LAP and autophagy share several molecular features, it is important to understand how LAP and autophagy are distinct at a molecular level. Here, we will explore the formation of the class 3 PI-3-kinase complex, unique to LAP, and how its activity recruits the ligase complex (common to LAP and autophagy) in a manner that is distinct from that of autophagy. 2. How does LANDO differ from conventional autophagy and LAP, and how does it influence cellular processes? We have identified a process, LANDO, distinct from LAP and autophagy, which nevertheless uses several of the proteins involved in each. We have found that this process is required for the recycling of several surface receptors to the plasma membrane following their internalization, even in non-phagocytic cells. We will interrogate LAP and autophagy proteins for their roles in LANDO and explore how these and other proteins known to be involved in receptor recycling influence cellular functions, including engulfment and inflammatory responses. 3. How do LAP and LANDO influence a model of Alzheimer’s Disease? Here, we will focus on the roles of LAP and LANDO in the clearance of amyloid by myeloid cells in the brain, and the consequences of defective LAP and/or LANDO for neuro-inflammation and degeneration. While studies of the decline of autophagic responses with age have been linked to disease, ours will be the first to do so in the context of these processes. LAP, LANDO, and autophagy share several molecular features but are distinct, and our studies proposed will reveal how these distinctions influence health and disease at the molecular, cellular, and organismal levels.

吞噬作用和自噬的古老过程是作为养分获取机制和 病原体防御，在某些情况下它们的功能机械相交。就是这样 LC3相关的吞噬作用（LAP），在这种过程中，自噬途径的某些组成部分是 招募到吞噬体中，以在该单个膜上降低LC3分子。圈和规范的自噬 在分子，细胞和有机水平上是不同的。由于我们发现了这个过程十一年 以前，在对各种细菌和真菌的免疫调查中暗示了膝盖，在其他几种 生理和疾病环境。我们还确定了与LC3相关的相关但独特的过程 内吞作用（Lando），其作用于参与阿尔茨海默氏病（AD）的B淀粉样蛋白的内吞作用。 该应用将探讨膝盖和兰多的机制及其在AD中的髓样反应中的作用。 我们选择了一个AD模型，其中询问膝上/陆地缺陷在髓样细胞中的影响 体内和无细胞系统中膝盖的核心生物化学。我们设想了该项目的三个目标。 1。什么 膝盖的机制是否将其与常规自噬区分开？因为膝盖和 自噬共享几个分子特征，重要的是要了解膝盖和自噬如何不同 在分子水平。在这里，我们将探索3类Pi-3-激酶复合体的形成，膝盖独有的 以及其活性如何以不同的方式报告连接酶复合物（膝盖和自噬） 从自噬。 2。兰多与常规自噬和膝盖有何不同，以及如何 它会影响细胞过程吗？我们已经确定了一个与膝盖不同的过程，Lando和 自噬，它仍然使用了每种涉及的几种蛋白质。我们发现这个过程 在其内部化后，几个表面受体回收到质膜需要 即使在非孢子细胞中。我们将询问膝盖和自噬蛋白在Lando和 探索这些已知参与受体回收的这些蛋白质和其他蛋白质如何影响细胞功能， 3。膝盖和Lando如何影响 阿尔茨海默氏病？在这里，我们将重点介绍Lap and Lando在清除淀粉样蛋白的角色上 大脑中的髓样细胞，以及神经炎症和/或Lando有缺陷的后果和/或 退化。尽管随着年龄的年龄的自噬反应下降的研究与疾病有关 我们将是第一个在这些过程中这样做的。圈，兰多和自噬分享几个 分子特征，但截然不同，我们提出的研究将揭示这些破坏如何影响健康 和分子，细胞和有机水平的疾病。